The research is directed toward the design and development of general strategies for the syntheses of oxygenated natural and unnatural products possessing biological activity. The investigation of synthetic applications of dipolar cycloadditions involving nitrile oxides will be continued. Another area of current interest will be in the extension of a general synthetic strategy that features the use of substituted furans as latent 1,4-dicarbonyl compounds and as highly useful intermediates for the stereoselective construction of functionalized hydropyrans, hydroxylated piperidines, and other important oxygenated cyclic and acyclic synthons. The methodology, which is developed during the course of these studies, will be applied to the total syntheses of: (a) the erythronolides A and B, the aglycones of the medicinally important macrolide antibiotics erythromycins A and B; (b) tylonolide, the aglycone of the macrolide antibiotic tylosin; (c) phyllanthocin, the aglycone of the antileukemic and antimelanoma glycoside phyllanthoside; (d) the pseudomonic acids A, B, and C, important antibiotics and antimicrobial agents, which are also competitive inhibitors of isoleucyl-tRNA synthetase; (e) the higher monosaccharides KDO, an eight carbon sugar that links the lipid section to the interior carbohydrate section of lipopolysaccharides of Gram-negative bacteria, and lincosamine, the saccharide subunit of the clinically important antibiotic lincomycin; (f) the polyhydroxylated alkaloids including nojirimycin, 1-deoxynor-jirimycin, 2(S)-carboxy-3(R),4(R),5(S)-trihydroxypiperidine, nojirimycin B and 1-deoxymannojirimycin, which have been shown to inhibit the glycosidases and mannosidases involved in the processing pathways that result in oligosaccharide maturation; and (g) breynogenin, an aglycone of the breynins A and B, sulfur containing glycosides that exhibit significant hypocholesterolemic activity. Reasonable quantities of selected synthetic intermediates and analogues of the above natural products for biological screening. Agreements to test various compounds for biological activity have been established with McNeil Laboratories, the Upjohn Company, Shell Development Laboratories and Chevron Chemical Company, all of which have already screened compounds from other NIH supported projects. Those substances which might exhibit anticancer activity will be submitted to the National Cancer Institute for evaluation as potential anticancer agents.